A well-known problem with the administration of peptides is that they are susceptible to acid hydrolysis and enzymatic degradation when administered orally. For this reason, parenteral administration has been the most widely used method; in the case of peptides of higher molecular weight, the parenteral route has provided the only effective means of administration. However, administration by injection is both inconvenient and unpleasant for the patient, particularly when injections must be repeated regularly over protracted periods.
A significant limitation to nonparenteral administration of many peptides, particularly those of higher molecular weights, is that they are poorly absorbed across the mucosal membranes which line the exposed surfaces of the oral, rectal, and vaginal orifices, the cornea of the eye, and the gut; thus the bioavailability of peptides after nonparenteral administration to mucosal surfaces often is very low. Consequently, various types of absorption promoters have been investigated which are claimed to have peptide absorption-enhancing properties. However, a recognized problem with absorption promoters is that they can cause irritation or tissue damage at the site of administration.
Among numerous possible drug delivery systems, emulsions occasionally have been proposed as pharmaceutical formulations for administration of peptides and proteins. In most cases those emulsions may be characterized as water-in-oil microemulsions, which are thermodynamically stable and usually self-emulsifying; see Cho et al., WO 90/03164; Cho et al., WO 91/14454; Affinity, WO 92/18147; Riley, U.S. Pat. No. 5,055,303; Ritschel, Meth. Find. Exp. Clin. Pharmacol. 13: 205-220 (1991). In each of these cases, the internal dispersed phase containing the protein typically is aqueous and the continuous phase typically is lipoidal.
Other types of microparticulate drug delivery systems also have been proposed as suitable for oral administration of therapeutic proteins, such as microspheres (WO 93/00077), lipospheres (Domb, U.S. Pat. No. 5,188,837), microcapsules (EP 442671), liposomes (LTI, WO 91/05545), or other lipid vesicles (Yoshida et al., EPA 140,085). It has been postulated that particles in the appropriate submicron size range in and of themselves enhance transport through the intestinal mucosa. However, this hypothesis is disputed by other experts in delivery systems for biopharmaceuticals; see Davis, J. Pharm. Pharmacol. 44: 186-190, (1992).
Individually, various components of emulsions have been considered as candidates for improving bioavailability of peptides. Thus, oral lipid medicinal compositions have been disclosed (Liedtke, U.S. Pat. No. 5,120,710) utilizing a semi-solid lipid component combined with a solid water soluble component. Surfactants of many types have been utilized as promoters of peptide absorption (EP 115627; GB 2,127,689; and U.S. Pat. No. 4,548,922). However, such surfactants have deleterious effects on the intestinal mucosa and may not be safe for their designated purpose.
Emulsification with a natural emulsifier derived from mammalian milk has been suggested as a method to circumvent the utilization of harmful surfactants (Yoshiaki et al., EP 0 494 654). These emulsions are not produced in the highly relevant submicron size range; rather, particles below 1 .mu.m are intentionally excluded.
Other emulsions have been disclosed in the submicron size range, but which necessarily contain specific ingredients such as lysophosphatidylcholine (Yesair, WO 92/03121).
Zerbe et al., WO 93/00076, disclose a drug delivery system consisting of a suspension of microparticles having a spherical core composed of a biopolymer, preferably a protein such as albumin or gelatin, which typically has been crosslinked or denatured to maintain its structural coherency. The spherical core may be combined with a bioadhesive polymer.
Riley, U.S. Pat. No. 5,055,303, discloses a bioadherent emulsion of the water-in-hydrophobic phase type, wherein the continuous hydrophobic phase is a solid fat. Bioadhesion is not attributed to a specific adherent component, but rather is apparently ascribable to the viscosity of the solid continuous phase.